(Philadelphia,
PA) - In the search to understand the nature of stem
cells, researchers at the University of Pennsylvania
School of Medicine have identified a regulatory gene
that is crucial in maintaining a stem cell's ability
to self-renew. According to their findings, the Foxd3
gene is a required factor for pluripotency - the ability
of stem cells to turn into different types of tissue
- in the mammalian embryo. Their research is presented
in the October 15th issue of the journal Genes and
Development.

"Stem cells represent a unique tissue type with
great potential for disease therapy, but if we are to
use stem cells then we ought to know the basis of their
abilities," said Patricia Labosky, PhD,
an Assistant Professor in the Department of Cell and
Developmental Biology.

"Among the stem cell regulatory genes, it appears
that Foxd3 gene expression keeps stem cells from
quickly differentiating - that is, developing into different
types of tissue - holding back the process so that an
embryo will have enough stem cells to continue developing
normally."

To study the function of the Foxd3 gene, Labosky
and her colleagues generated mice with an inactivating
mutation in the gene, and then analyzed those mice to
determine the role of the Foxd3 protein. Foxd3-deficient
embryos do not survive very long. While part of the
yolk sac forms, the inner cell mass that contains all
the cells that make up the body of the developing embryos
fails to expand enough to produce the embryo and some
of the supportive tissues. Without Foxd3, the
mouse embryos simply could not maintain enough stem
cells to survive a crucial point in their development.

"Our findings implicate Foxd3 as one of
the few genes serving as a 'master switch' of the developing
embryo," said Labosky. "These genes determine
the fate of cells by turning on or off other genes in
response to signals in the embryo."

Foxd3 joins previously identified genes, such
as Oct4,Fgf4, and Sox2, which
control the pluripotency of embryonic stem cells in
the early stages of embryogenesis. In their experiments,
Labosky and her colleagues found that these genes are
still expressed despite the lack of Foxd3. This
suggests Foxd3 functions either downstream of
Oct4, Fgf4 and Sox2, or along a parallel
pathway.

The researchers determined that normal embryonic development
can be restored by adding non-mutant embryonic stem
cells to the Foxd3-mutant embryos, indicating
that Foxd3 acts in the inner cell mass and its
derivatives. According to Labosky, Foxd3 is a
key regulator of mammalian stem cells, with a clear
counterpart in humans. Foxd3 gene expression
is a diagnostic characteristic of human embryonic stem
cells, suggesting that the gene may function in a similar
fashion in mouse and human cells.

"If we are to take advantage of stem cells as a
clinical therapeutic, then it is absolutely vital to
identify the key regulatory genes such as Foxd3
that control the process of cell differentiation,"
said Labosky. "Once we understand how these genes
function we are that much closer to being able to mold
stem cells to meet our needs."